new discoveries for a healthy future

Interleukin-33: A Potential Breakthrough in the Treatment of Alzheimer’s Disease?

Alzheimer’s disease—the most common form of dementia—is an irreversible, progressive disorder that slowly destroys memory and thinking skills, and eventually the ability to carry out the simplest tasks. It’s currently ranked as the sixth leading cause of death in the United States, but recent estimates indicate that the disorder may rank third, just behind heart disease and cancer, as a cause of death for older people.

Gerontologist Laura Wayman says: “I tell family caregivers that they need to start thinking of a loved one’s brain like a piece of Swiss cheese, which has random holes in it. The disease is robbing them of brain cells that allow them to function normally.” She explains that when a person with Alzheimer’s tries to access the functionality of their brain, they may either access “cheese” (a lucid moment), or a “hole” (a confused moment in which they frantically try to compensate for memory loss with bizarre behaviors, often linked to feelings and memories from their past).

Greg O’Brien, author of “On Pluto: Inside the Mind of Alzheimer’s,” and a patient-advocate for the Alzheimer’s Association, is documenting his own Alzheimer disease while he still can: “Daily medications serve to slow down the progression of the disease and to help control the rage on days when 60 percent of my short-term memory is gone in 30 seconds—days when I hurl the phone across the room, a perfect strike to the sink, because in the moment I don’t remember what number to dial. Or when I smash the lawn sprinkler against an oak tree in the back yard because I can’t recall how it works, or when I push open the flaming-hot glass door to the wood stove in the family room bare-handed to stoke the fire because my mind told me it was a good idea, resulting in a second-degree burn. Or simply when I cry privately, the tears of a little boy, because I fear that I’m alone, nobody cares and the innings are beginning to fade.”

According to the National Institute on Aging, during the very early stage of disease, people with Alzheimers’ disease do not show any symptoms—however, during this time, several changes take place in the brain. Abnormal deposits of proteins form amyloid plaques and tau tangles throughout the brain. Consequently, once-healthy neurons begin to work less efficiently. Amyloid plaques are the build up of sticky proteins called beta amyloid, and tau tangles are twisted strands of a protein called tau. Over time, neurons lose their ability to function and communicate with each other, and eventually die. Before long, the damage spreads to a nearby structure in the brain called the hippocampus, which is essential in forming memories. As more neurons die, affected brain regions begin to shrink. By the final stage of Alzheimer’s disease, damage is widespread, and brain tissue has shrunk significantly.

Although there are medicines that can ameliorate symptoms of the disease, there is no known cure for Alzheimer’s disease. Now, results from a new study carried out in a mouse model indicate that a cytokine called interleukin-33 (IL-33) can reverse Alzheimer’s disease-like pathology and cognitive decline. The study (IL-33 ameliorates Alzheimer’s disease-like pathology and cognitive decline) was published a few days ago (April 18, 2016) in the journal Proceedings of the National Academy of Sciences USA.

Eddy Liew, one of the study authors, said in a press release: “IL-33 is a protein produced by various cell types in the body and is particularly abundant in the central nervous system (brain and spinal cord). We carried out experiments in a strain of mouse (APP/PS1) which develop progressive Alzheimer’s-like disease with ageing. We found that injection of IL-33 into aged APP/PS1 mice rapidly improved their memory and cognitive function to that of the age-matched normal mice within a week.”

IL-33 appears to work by mobilizing microglia—the primary immune cells of the central nervous system. These cells are highly similar to peripheral macrophages. They act as the major inflammatory cell type in the brain, and respond to infectious microbes and injury by becoming “activated”—a process whereby they rapidly change morphology, proliferate and migrate to the site of infection/injury where they engulf and destroy infectious microbes as well as remove damaged cells.

According to the new study, microglia surround the amyloid plaques, take them up and digest them, thus reducing their number and size. In addition, the study results show that IL-33 treatment inhibits inflammation in brain tissue—inflammation has been shown earlier to potentiate plaque and tangle formation. Therefore, IL-33 not only helps to clear the amyloid plaque already formed, but also prevents the deposition of plaques and tangles.

How do these results obtained in mice relate to humans? Previous research suggests that IL-33 may play a role in the development of Alzheimer’s disease in humans—genetic studies show an association between IL-33 mutations and Alzheimer’s disease in European and Chinese populations. Furthermore, the brain of patients with Alzheimer’s disease contains less IL-33 than the brain from non-Alzheimer’s patients.

However, Liew added: “Exciting as it is, there is some distance between laboratory findings and clinical applications. There have been enough false ‘breakthroughs’ in the medical field to caution us not to hold our breath until rigorous clinical trials have been done. We are just about entering Phase I clinical trial to test the toxicity of IL-33 at the doses used. Nevertheless, this is a good start.”

Alzheimer’s disease is a progressive dementia that is found to be irreversible due to non functioning neurons and a build up of plaque that shuts of functions in the brain causing memory loss and confusion. This therapy for Alzheimer patients can be life changing because, most Alzheimer patients have a low concentration of IL-33, If a patient was administered IL-33 protein it would help to clear the amyloid plaque already formed, but also prevents the deposition of plaques and tangles to continue mobilizing microalgia to prevent against inflammation and plaque build up. Although in the early stages of this disease is undetectable, I believe for people of the age 55 and older should be screened for this disease and if it is found that they are in the early stages they should be administered IL-33 to stop the progression for the disease. Early detection for all diseases and cancers end up saving more lives granted if there is a cure or therapy available. Not much is known about the cause of Alzheimer’s disease but therapy is the best way to start figuring out the root of the problem.

Alzheimer’s disease is one of the leading causes of death in the United States and typically effects people of older age. Its effects can be not only devastating to the patient but also to the patient’s family. The patient’s brain is often compared to as Swiss cheese, and they have gaps in their memory due to holes in their brain which gradually progresses over time. The family has to watch as their loved one begins to first forget their name and then eventually forget them altogether. Their confused memory can often cause them to have outburst of rage or get themselves in dangerous situations. Alzheimer’s is due to a buildup of amyloid plaque and tau tangles within their brain which causes dysfunction in neuronal transmission. Inflammation which is part of innate immunity is commonly associated with worsening the disease in Alzheimer’s patients. In the study IL-33 ameliorates Alzheimer’s disease-like pathology and cognitive decline, IL-33 is used to stimulate microglia which are the phagocytic cells of the brain. The stimulated microglia are able to enhance their phagocytic activity against amyloid plaques and express anti-inflammatory genes to decrease an inflammatory response. It appears as though interleukins could be a promising breakthrough therapy against Alzheimer’s. In another study titled Pharmacological antagonism of interleukin-8 receptor CXCR2 inhibits inflammatory reactivity and is neuroprotective in an animal model of Alzheimer’s disease, it also looks at exploring interleukins as a treatment option. The study states that IL8 is one of the largest increasing inflammatory factors in patients with Alzheimer’s disease. It commonly causes an increase of inflammatory cytokines as well. The study shows that by blocking IL8 from interacting with its receptor CCR2 it greatly reduced inflammation in rats that had been receiving intrahippocampal injection of amyloid-beta and reduced neuronal damage.

The usage of IL-33 in the treatment for Alzheimer’s disease would involve the utilization of a cytokine with dual functions. As Knox has already stated, this cytokine can provide both pro-inflammatory and anti-inflammatory functions. The expression of this cytokine in the central nervous system induces the proliferation of microglia as well as the production of the pro-inflammatory cytokines, IL-1ß and TNF∂, and the anti-inflammatory cytokines IL-10. The IL-33 cytokine enhances phagocytic activity by the microglia and has shown decreased secretion of ß-amyloid peptides as seen on cell based assays. It is fair to say that IL-33 plays a large role in regulation of the immune functions in the central nervous system. The use of the anti-inflammatory properties should be the focus for future endeavors concerning Alzheimer’s due to the nature of the damaging effects of inflammation on the already damaged portions of the brain. By understanding and mimicking the anti-inflammatory cytokines and inducing increased phagocytosis by microglia, scientists may be able to control the immune cells and their functions to synergistically combat the plaques.

Just as the article states, the findings from this study should be taken with a grain of salt. Not only does this not imply that a cure is within reach but despite its potential, some of the possible effects of IL-33 can prove to be less than favorable. In the context of Alzheimer’s and the brain, IL-33 seems to be doing a pretty good job influencing microglia to reduce amyloid plaques and reduce inflammation. On the other hand the inflammation induced by the cells containing receptors for IL-33 can be quite damaging in many cases. High levels of IL-33 have been detected in people who suffer from asthma, certain skin conditions, and irritable bowel syndrome. IL-33 does, however, seem to pay a role in protection from damage due to atherosclerosis. It’s not to say that introducing IL-33 as a potential treatment for Alzheimer’s should no longer be considered. However, an appropriate balance between the improvement of the quality of life of Alzheimer’s sufferers and the possible damage to the rest of the body should be strived for.

For the past decade most research has focused mostly on eliminating the deposits of amyloid plaques and tau tangles. What this article describes is a fairly new hypothesis about neuroinflammation playing a role as well in the development of Alzheimer’s. Since there is data to support that Alzheimer’s may have some genetic factors (1), it makes me wonder if potential genetic factor could be the overproduction of microglia, over-excretion of inflammatory cytokines in response to the aforementioned protein formations, and/or an irregular expression of IL-33. I’ve also found a couple of articles and studies that dealt with how to treat Alzheimer’s disease but from a slightly different angle. A group of British researchers found that suppressing the production of microglia altogether by blocking the brain cell receptor CSF1R also inhibits the characteristic decay of Alzheimer’s (2). Perhaps a combination of both suppressing the production of microglia and increase levels of IL-33 in the brain could be the next big step in the treatment of Alzheimer’s.

Alzheimer’s has the highest incidence and prevalence rates in the U.S., having about 3 million cases per year. As the years go by, the number of cases are increasing, and as of yet, there is no definite cure. There has been research presenting novel ideas about anti-inflammatory cytokines, but have shown little success. One of those novel ideas was using the cytokine storm theory in order to reduce the beta amyloid plaques, which was not successful. In this study, scientists injected IL-10, an anti-inflammatory cytokine that should, in a cytokine storm, decrease the plaques in the mouse brain inflicted with Alzheimer’s. On the contrary, IL-10 had over-expressed apolipoprotein E, a protein that should aid clearing beta amyloid plaques. This protein, in turn, had bound to the plaques, increasing the build-up rate of the plaques in the mouse brain. Scientists had then blocked the expression of IL-10. Alzheimer’s-inflicted mice who had inhibited IL-10 levels began behaving like mice who were not affected with Alzheimer’s, which proved that blocking IL-10 not only reduced the rate of beta amyloid build-up, but also reduced the rate at which Alzheimer’s spread significantly.

Although the primary article provides a novel idea, I don’t believe it will be therapeutic. The article I presented showed that innate immunity may not always aid in targeting affected areas, but rather progress diseases. This is clearly shown in the APOE protein and how cytokines had promoted the expression of it. More research should be done with different targets, including IL-10, in order to come closer to possibly curing Alzheimer’s.

Immunotherapies, such as the IL-33 treatment suggested in the article, are being thoroughly investigated to treat Alzheimer’s disease. In comparison to other treatments for Alzheimer’s disease, immunotherapy is a safer option because it utilizes or enhances machinery already in one’s body, like interleukins, instead of introducing foreign chemicals. As magnificent as it seems, there are a couple of issues that still threaten the success of immunotherapy. An active immunity vaccine,AN1792, was developed in the 1990’s but development ceased when it was found that 6% of the trial group developed meningitis. IVIg is a treatment that includes injected human antibodies and unfortunately showed now decrease in progression. The main underlying issue with the vaccines is how to get the antibodies to the affected parts of the brain, especially since only 0.1% of antibodies made actually cross the blood-brain barrier. Researchers also have problems with the removal of amyloid plaques after neuron degeneration. It seems that the IL-33 treatment bypasses these issues and will hopefully be successful in the future.

Advancement in medicine has allowed humans to have a longer life which introduces us to newer health challenges such as Dementia caused by Alzheimer’s disease(AD). The article mentions that AD has been ranked the sixth leading cause of death in the United states. I personally have a close family member that suffers from this disease so it was exciting to read that there are scientist still working hard to find new approaches to come up with a solution. Alzheimer affects the individual’s memory, thinking, behavior and ability to perform day-to-day activities. AD not only affects the individuals that suffer from it but also the care givers. Between the cost of medications and general care, it takes a huge toll of the families of the individual. So any progress of understanding and potentially finding an effective medicine is exciting. As the researcher in the article mentioned, there have been many ‘false breakthroughs’ in these field. This made me to look into the potential risks of IL-33 based treatment. According to a research done by the University of Ferdowssi in Iran, there is a significant link between the IL-33 gene rs11792633 and risk of schizophrenia in Iranian population. This does raise a question of weather or not this link can be seen in other groups of population and if so will the IL-33 treatment mentioned in the article cause other mental health problems such as schizophrenia. I think more studies need to be done before doing clinical trails in humans.

Alzheimer is a very serious disease because it makes people forget very basic things such as even who they are. While this study was done on mice, and the authors asked questions about whether or not this could be applied to humans, previous studies have researching ways to slow the progress of the disease in humans by decreasing the beta-amyloid production and preventing it from aggregating.
First, because amyloid plaques play an important role in Alzheimer disease, they believe that the beta-amyloid production could be preventing by giving secretase inhibitors to the patients. In fact, secretases cut the APP into beta-amyloid so they believe that inhibiting those secretase production will reduce the production of beta-amyloid. For example, one drugs that is in trials actually to inhibit the secretase production is called LY-450139.
Another way they thought could help improve Alzheimer in patients, is to prevent the beta-amyloid from aggregating to form plaques, in case they are still produce. So consequently, scientists are looking for drugs that will block the oligomers from forming and prevent those plaques formation. Two drugs that are still in trials are PBT2 and Tramiprosate.
I believe that if scientists are able to produce the drugs mentioned above, and they find a way to administrate IL-33 as the article talked about, the risks for having Alzheimer will significantly decrease.

First of all, I like to salute the researchers for the good work. Having somebody close to me with Alzheimer’s, I know how hard it is for the patient and their loved one. Just imagine of having someone so close to you all your life, that person had always been an inspiration to you. As far as you remembered, that person was so strong and reliable but right now that he can’t even remember your’s name, or for the worst part, his name and if he had eaten five minutes ago. I watched my maternal grandfather wither away to just shells of himself, and it was horrible to bear witness to. I have faith that modern medicine will indeed someday find a solution to this terrible disease and this research finding may bring many people some hopes.

Even though this research and discovery are still under trial, but like the researchers said “this is a good start. I’m not an AD (Alzheimer’s disease) expert, so please correct me if I’m wrong. As far as I know, way before Alzheimer’s Disease goes all super-saiyan on you, you’ve got 10-20 years of this amyloid plaque buildup*. Plaques come about because of a misfolding of normal proteins in your brain; the misfolding makes them insoluble, and they clump up, and once these clumps form they don’t go away. These plaques then induce a misfolding in Tau proteins, which are involved in neuronal cytoskeletons esp. along axons. They’re vital to axoplasmic transport. Basically, without them, your brain wires fall apart. And so amyloid plaques seem to lead to Tau “tangles” and this lead to AD.

So if IL-33 stimulate and mobilizing microglia, allowing microglia to phagocytize the amyloid plaques as well as reduced inflammation, this should ultimately slow down AD progression. In theory, this sound to be quite compelling and interesting therefore I am quite interested to see what would this lead.

Alzheimer’s disease (AD) is a neurodegenerative disease that results in damage and loss of function of many major neuronal cells that could lead to diverse effects. One effect of AD is dementia, which is not only devastating to the patient but also their loved ones. Even though scientists are trying to determine the many potential risk factors and there role in disease progression, no cure still exists. According to the article, IL-33 usage as a therapeutic intervention in treatment of the disease not only can it improve the quality of life by restoring certain functions but it also can help prevent further plaque and tangle formation. This treatment if successful could raise hope for those affected. It is understandable the raised concern of many individual’s here about the risks associated with the treatment. This is because most treatment nowadays have high risk factors and less benefit. But it is also clearly known that some therapies comes with diverse risks and not everyone will have same response to treatment. The hope of many therapies is to increase benefit and reduce risk and I hope with many future clinical trials that this treatment could be a break-through with less risk associated with it.